Doethyl phenyl sulfonylureas

ABSTRACT

New (pyrazolo(3,4-b)pyridin-5-ylformamidoethyl)phenylsulfonylureas are useful as hypoglycemic agents.

United States Patent [151 3,697,527 Hoehn et al. 1 Oct. 10, 1972 [54]DOETHYL PHENYL SULFONYLUREAS [56] References Cited [72] Inventors: HansHoehn Tegernheim; Ernst UNITED TATES PATENTS Schulze, Regensburg, bothof Ger- S many 3,445,470 5/1969 Jucker et a1. ..260/292 [73] Assignee:E. R. Squibb & Sons, Inc., Prin- Prima'y Examiner Alan RotmanAttorney-Lawrence S. Levinson, Merle J. Smith, 22 Filed; p 970 Donald J.Perrella and Burton Rodney [21] Appl. No.: 94,522 7 ABSTRACT New[pyrazolo[3,4-b]pyridin-5-ylformamidoethyl]- 52 U.S.Cl. ..260/294.8 c,260/2955 B, 424/266 phenylsulfonylureas are useful as hypoglycemic 51Int. Cl. ..C07d 31/44 agents [58] Field of Search ..260/294.8F

9 Claims, No Drawings 1 DOETHYL PHENYL SULFON'YLUREAS SUMMARY OF THEINVENTION The present invention relates to new [pyrazolo[3,4- b]-pyridin-S-foramidoethyl]phenylsulfonylureas and their salts. These newcompounds have the-formula DETAILED DESCRIPTION OF THE INVENTION Thelower alkyl groups represented by the symbols include straight andbranched chain aliphatic hydrocarbon groups ofup to seven carbon atomssuch as methyl, ethyl, propyl, isopropyl, butyl, t-butyl and the like.The phenyl-lower alkyl groups represented by R are radicals in which aphenyl group is attached to a hydrocarbon chain like those above, forexample, benzyl, phenethyl and the like.

The phenyl and phenyl-lower alkyl groups may be simply substituted withone or two substituents on the aromatic ring. T'hus'they may berepresented as (R phenyl or (R ),,-phenyl-lower alkyl, wherein R ishydrogen, lower alkyl, halogen, or lower alkoxy andn is l or 2. Thelower alkyl groups are the same as already described. The lower alkoxygroups represented by both R and R are of the same kind, e.g., methoxy,ethoxy, propoxy, isopropoxy and the like. The lower al-' kenyloxy groupsrepresented by R are ether groups of the same kind having amonounsaturated hydrocarbon chain. All four halogens are contemplated,but chlorine and bromine are preferred in all cases.

The cycIo-lower alkyl groups represented by R, are the 3- to 6- memberedcycloaliphatic groups cyclopropyl, cyclobutyl, cyclopentyl andcyclohexyl.

The new compounds are formed by the following series of reactions.

A 5 -aminopyrazole of the formula wherein R is the same'as previouslydefined and-R and R each is hydrogen, lower alkyl, phenyl or phenylloweralkyl. The cyclization is effected by heating at a temperature of'aboutto 130C. in an inert liquid solvent, e.g., an alcohol like ethanol,butanol or the like, preferably in the presence of a catalyst, e.g.,alcoholates like alkali metal alcoholates, particularly butylates'suchas sodium butylate.

This Saminopyrazole is reacted with an alkoxymethyleneimalonic acidester of theformula This may be effectedby heating the 'reactants'at atemperature of the order of C. fors'everal hours, and results in acompound of the formula 1k 0 O O-lower alkyl The alkoxymethylene malonicacid esters of formula IV are known compounds and are produced likeethoxymethylene malonic acid diethyl ester [Organic Syntheses 28, 60-62(1948)].

Cyclization of a compound of formula V, either in an inert solvent'suchas diphenyl ether at a'temperatur'e of about 230-260 C. or by refluxingwith a phosphorus halide like phosphorous oxychloride, providescompounds of formula R C O O=lower alkyl I R 1 i in which R is hydroxyin the first case and halogen in the second case, depending on themethod of cyclization. Treatment of a compound of formula VI, in which Ris a hydroxy group, with an alkylating agent such as a lower alkylhalidelike ethyl iodide in an inert organic solvent and in the presence of analkali metal carbonate provides the 4-lower alkoxy compound.

Alternatively, instead of alkylating the 4-hydroxy compound of formulaVI, the 4-halogenated product may also be converted to the4-alkoxy-1H-pyrazolo[ 3,4-b]pyridine-5-carboxylic acid ethyl ester bymeans of a metal alcoholate. The free acids corresponding to the estersof formula VI may be obtained from the ester by treatment with aqueoussodium hydroxide solution.

Conversion of the free acid, in which R represents hydrogen, loweralkoxy or chlorine, by means of thionyl chloride produces a compound ofthe formula Br I HzN-CHz-OHr-Q-S mm (VIII) and results in a compound offormula Alternatively, a compound of formulaIX may be prepared byreacting the free acid referred to above with a compound of formula VIIIin the presence of isobutyl-chloroformate of the formula The sulfonylureas of this invention are then prepared by reacting thebenzenesulfonamide of formula IX or a salt thereof, e.g., an alkalimetal salt, with an R,-substituted isocyanate (e.g., R.,N=C=O which ispreferred) or R,,-substitutedwcarbamic acid esters, thiocarbamic acidesters, carbamic acid halides or ureas.

' The compounds of formula I form basic salts, e.g.,

with metals such as alkali metals like sodium and potassium, alkalineearth metals like calcium magnesium, barium and the like. The salts areformed by conventional methods, e.g., by treatment with a metalalcoholate in an alcohol, e.g., sodium ethylate in ethanol solution. Theformation of a salt is frequently useful in purifying the product.Neutralization of the salt gives the free sulfonylurea again.

The sulfonylureas obtained from this invention are useful ashypoglycemic agents and are characterized by a strong and long-lastingblood-glucose lowering action in various mammalian species. Thehypoglycemic activity of these compounds may be evaluated, e.g., inrats, mice, rabbits, dogs and the like, by utilizing W.S. Hoffmannspotassium ferricyanide-potassium ferrocyanide oxidation-reductionreaction in an Autoanalyzed [1. Biol. Chem. 120, 51 (1937) or theenzymatic method described by A. Keston (abstract of Papers, 129thMeeting Amer. Chem. Soc., p.3lc) and F. H. Schmidt [Internist4, 554,(1963)].

For this purpose, a compound or mixture of compounds of formula I, ornon-toxic, physiologically acceptable salt thereof, may be administeredorally or parenterally in a conventional dosage form as tablet,

capsule, injectable or the like. A single dose, or

preferably 2 to 4 divided daily doses, provided on a basis of about I to50 mg. per kilogram per day, preferably about 2 to mg. per. kilogram perday, is appropriate. These may be conventionally formulated in an oralor parenteral dosage form by compounding about 10 to 250 mg. per unit ofdosage with conventional vehicle, excipient binder, preservative,stabilizer, flavor or the like as called for by accepted pharmaceuticalpractice.

The following examples are illustrative of the invention. Other membersof the group may readily be produced in similar fashion by replacing thestarting materials with appropriately substituted 1 5- aminopyrazoles orisocyanates. All temperatures are on the centigrade scale.

EXAMPLE 1 1-Cyclohexyl-3 -[[p?[2-[(4-ethoxyl-ethyl- 1 H-pyrazolo[3,4-b]-pyridin-5-yl)formamido]ethyl]phenyl] sulfonyl]urea a.l-ethyl-5-pyrazolyl)amino]methylene]malonic acid diethyl ester 245 g. ofl-ethyl-5-aminopyrazole (2.2 mol.) and 476 g. of ethoxymethylene malonicacid diethyl ester (2.2 mol.) are heated to 120 (bath temperature) for 2hours with stirring. The ethanol formed by this reaction is removed bymeans of a water aspirator. Then vacuum distillation (hp l54-160) yields520 g. (84 percent of theory) of a quickly crystallizing oil ofl-ethyl-5-pyrazolyl)amino1methylene]malonic acid diethylester, m.p. -53. The compound is recrystallized from N-hexane, m.p. -5 7.

b. l(-ethyl-4-hydroxyl -H-pyrazolo[ 3 ,4-b]pyridine- 5-carboxylic acidethyl ester 253 g. of [[(1-ethyl-5-pyrazolyl)amino]methylene] malonicacid diethyl ester (0.09 mol.) are dissolved in 770 g. of diphenylether. The reaction mixture is heated to 235-250 (bath temperature) andallowed toreact at this temperature for l to 2 hours, while theresulting ethanol is continuously distilled off. The last amount ofalcohol is removed by means of a water aspirator. The diphenyl ether isseparated by distillation with a fractionating column in vacuo. Thel-ethyl-4-hydroxy-lI-I- pyrazolo[ 3,4-blpyridine-S-carboxylic acid ethylester is obtained at b.p. 1 151 20, yield 195 g. 92 percent of theory,m.p. 85-87. The compound is recrystallized from benzine 90 to 100), m.p.8789.

c. 4-ethoxy-1I-I-pyrazolo[3 ,4-b]pyridine-5-carboxylic acid ethyl ester400 g. of well pulverized potassium carbonate and 300 g. of ethyl iodideare introduced into a solution of 259 g. (1.1 mol.)l-ethyl-4-hydroxy-lH-pyrazolo[3,4-

b]pyridine-5carboxylic acid ethyl ester in 1.7 of dimethylformamide. Thereaction mixture is stirred for 7 hours at 65 and filtered off undersuction, while hot, from the excess potassium carbonate. Upon standingovernight, 165 g. of ethyl ester crystallizes from the solution, m.p.ll2l 15. After evaporation of the mother liquor, and additional g. areobtained. The total yield amounts to percent of the theory. The 4-ethoxyl -ethyll I-I-pyrazolo[3 ,4-b]pyridine-5-carboxylic acid ethylester is recrystallized from benzine, (l00), m.p.,l l3-l 15.

d.. 4-ethoxy- 1 H-pyrazolo[3 ,4-pyridine-5-carboxylic acid 26.3 g. of4-ethoxy-l-ethyl-1-I-I-pyrazolo[3,4-b]- pyridine-5-carboxylic acid ethylester (0.1 mol.) is hydrolyzed with 375 ml. of aqueous sodium hydroxide(1.5 N.) room temperature with stirring for 10 hours. Afteracidification with hydrogen chloride, 21.8 g. of 4 ethoxyl -ethyllH-pyrazolo[3 ,4-b]pyridine-5-carboxylic acid, m.p. l98l99, (yield 92.5percent) are obtained.

e. 4-ethoxy-l-ethyl-ll-l-pyrazolo[3,4-b]pyridine-5- carbonyl chloride26.5 g. of 4-ethoxy-l-ethyl-lH-pyrazolo[3,4-b] pyridine-S-carboxylicacid (0.11 mol.) and 150 ml. of thionyl chloride are refluxed for 7hours. The thionyl chloride is removed by means of a water aspirator.The residue, weighing 27 g. (96 percent of theory), contains the crude4-ethoxyl -ethyll H-pyrazolo[3 ,4-b] pyridine-Scarbonyl chloride, m.p.1l6-l20, which can be used without further purification for the nextreaction step'. A sample recrystallized from cyclohexane melts at l 22-l24.

f. 4-[ B-( 4-ethoxy- 1 -ethyll l-l-pyrazolo[ 3 ,4-b]pyridine-5-formamido)ethyl]benzenesulfonamide 29.4 g. ofp-(B-aminoethyl)benzenesulfonamide (0.14 mol.) are added to 17.5 g.4-ethoxy-l-ethyl-1H- pyrazolo[3,4-b]pyridine-5-carbonyl chloride (0.07mol.) suspended in 200 ml. of anhydrous pyridine. The reaction mixtureis stirred for two hours at room temperature. The precipitate consistingof 4-[fl-(4-ethoxyl-ethyl- 1 l-l-pyrazolo[3 ,4-b]pyridine-S-formamido)ethyl]-benzenesulfonamide and p-(B-aminoethyl)benzenesulfonamide hydrochloride, is filtered off undersuction and washed with pyridine and ether. In order to remove thehydrochloride of the starting sulfonamide, the precipitate is washed offwith water and then dried, yield g., m.p. 220222. By evaporating themother liquor and treating the residue with water, an additional 10 g.are obtained. The total yield of4-[fi-(4-ethoxy-l-ethyl-lH-pyrazolo[3,4-b]pyridine-5-formamido)ethyl]benzenesulfonamide amounts to g. 69 percentof theory. The compound is recrystallized from dioxane, m.p. 221-222. g.l -Cyclohexyl-3-[ [p-[2-[(4-ethoxy-l-ethyl-1H-pyrazolo-l3,4-b]pyridin-5-yl)formamido]ethyl]phenyl]su1fonyl]urea 4.2 g.of 4-[B-(4-ethoxyl-ethyl-l l-l-pyrazolo[3,4-b]pyridine-S-formamido)ethyl]benzenesulfonamide (0.01 mol.) and 2.8 g. ofwell pulverized potassium carbonate (0.02 mol.) are suspended in 75 ml.of acetone. The mixture is refluxed for one hour, then 1.3 g. ofcyclohexylisocyanate (0.01 mol.) are added rapidly, one drop at a time.The whole is refluxed for 4 hours with stirring. After cooling, theprecipitate is filtered off under suction, washed with acetone and inturn dissolved in 150 ml. of hot water. Undissolved matter is separatedby filtration, and the filtrate is acidified with dilute hydrochloricacid. The l-cyclohexyl-3-{[p-[2- [(4-ethoxy- 1 -ethyl l l-l-pyrazolo[3,4-b]pyridin-5- yl)formamido]-ethyl]-phenyl]sulfonyl]urea whichprecipitates in the form of crystals melts after recrystallization froma mixture of methanol and dioxane at 2 l 3-2 14. Yield 3.7 g. 68 percentoftheory.

For the preparation of the sodium salt, thelcyclohexyl-3-[[p-[2-[(4-ethoxy-l-ethyl)-1H-pyrazolo]3,4-b1pyridin-5-yl)formamido]-ethyl]phenyl]sulfonyl]urea istreated with an equimolar amount of sodium ethylate in an ethanolsolution. At room temperature, the sodium salt precipitates in the formof white crystals melting at l99-20l.

EXAMPLE 2 l-Cyclohexyl-3-[ [p-[2-[(4-ethoxyl -ethyl-1H- pyrazolo[ 3,4-b]-pyridin-5-yl)formamido]ethyllphenyl ]sulfonyl]urea a. 4-chlorol-ethy1- l H-pyrazolo[ 3,4-b]pyridine-5- carboxylic acid ethyl ester Amixture of 12 g. of [[l-ethyl-S- pyrazolyl)amino]methylene]-malonic aciddiethyl ester (0.043 mol.) and ml. of phosphorus oxychloride is refluxedfor 10 hours. The excess phosphorus oxychloride is removed in vacuo andthe oily residue is treated with 50 ml. of water which causes the oil tobecome crystalline. The solid material is filtered off under suction anddried in a desiccator; yield 8.5 g. 79 percent of theory. The4-chloro-l-ethyl-1I-lpyrazolo[3,4-b]pyridine-S-carboxylic acid ethylester is recrystallized from N-hexane, m.p. 62.

Alternatively, the 4-chloro- 1 -ethyll l-l-pyrazolo[ 3 ,4-b]-pyrimidine-5-carboxylic acid ethyl ester is prepared as follows: Amixture of 23.5 g. of l-ethyl-4-hydroxy-ll-l-pyrazolo[3,4-bl-pyridine-S-carboxylic acid ethyl ester (0.1 mol.)and 150 ml. of phosphorus oxychloride is refluxed for 4 hours. Theexcess phosphorus oxychloride is removed by means of vacuumdistillation. As soon as the phosphorus oxychloride is removed, the oilyresidue solidifies on cooling. It is treated with water and filtered offunder suction (24.5 g.), m.p. 55-60. The 4-chloro- 1-ethyl-ll-l-pyrazolo[ 3,4-b1pyridine-5- carboxylic acid ethyl ester isrecrystallized from N-hexane (22.5 g. 87 percent), m.p. 62.

b. 4-ethoxyl -ethyll l-l-pyrazolo[ 3 ,4-b]pyridine-5- carboxylic acidand ethyl ester 25.4 g. of 4-chloro-l-ethyl-lH-pyrazolo[3,4-b]pyridine-S-carboxylic acid ethyl ester (0.1 mol.) are added to asolution of 2.3 g. of sodium (0.1 mol.) in 250 ml. of ethanol. Thismixture is kept at room temperature for 12 hours. After this, theseparated sodium chloride is filtered off under suction and the filtrateis evaporated to dryness in vacuo. The residue, 4-ethoxyl-ethyllH-pyrazo1o[3,4-b]pyridine-S-carboxylic acid ethyl ester, isrecrystallized from benzine (90100), m.p. ll3, yield 24.8 g. 94.5percent of theory. Hydrolysis of this product, according to theprocedure of example 1(d), provides 4-ethoxy-l-ethyl-1H- pyrazolo[3,4-b]pyridine-S-carboxylic acid.

0. l-Cyclohexyl-3-[ [p-[2-[(4-ethoxy-1-ethyl-l H- pyrazolo-[3,4-b]pyridin-5-yl)formamido]ethyl]phenyl]sulfonyl] A solution of 23.5g. of 4-ethoxy-l-ethyl-1H- pyrazolo-[3,4-b]pyridine-5-carboxylic acid(0.1 mol.) in 300 m1. of chloroform and 20 m. of triethylamine is cooledto 0. At this temperature, 19 g. of isobutylchloroformate is added onedrop at a time. The whole is stirred for two hours during which time thetemperature may increase to 15. A suspension consisting of 20 g. ofp-(B-aminoethyl)benzenesulfonamide (0.1 mol.) in 200 ml. of chloroformand 20 ml. of triethylamine is added to the mixture. The mixture isstirred at room temperature for four hours, the precipitate is filteredoff under suction and washed with chloroform. With the amount isolatedfrom the mother liquor, 26.5 g. of 4-[B-(4-ethoxy-l-ethyl-lH-pyrazolo [3,4-b] py ridin-S-formamido )ethyl ]benzenesulfonamide, m.p. 2l32l4 isobtained which in turn is converted to l-cyclohexyl-3-[ [p-[ 2-[l-ethyl-l H- pyrazolo[ 3 ,4-b pyridin-5-yl)formamido ethyl]phenyl]sulfonyl]urea according to the procedure of Exam- P (g)- EXAMPLES1-Cyclohexyl-3-[[p-[2-(4-chloro-1-ethyl-3-methyl-ll-lpyrazolo-[3,4-b]pyridin-S-yl)formamido]ethyl]phenyl]sulfonyl]urea a. l-ethyl-3-methyl-5-pyrazolyl)amino] methylene]malonicacid diethyl ester 12.5 g. of 1-ethyl-3-methyl -aminopyrazole (0.1 mol.)and 21.6 g. of ethoxymethylene malonic acid diethyl ester (0.1 mol.) areheated to 120 (bath temperature) for 2 hours with stirring. The ethanolformed by this reaction is removed by means of a water aspirator. Thenvacuum distillation (b.p. l52l53) yields 24.0 g. (81.5 percent oftheory) of a quickly crystallizing oil,[[(1-ethyl-3-methyl-5-pyrazolyl)-amino] methylenelmalonic acid diethylester, m.p. 6067. The product, recrystallized from benzine (90l00),melts at 6970.

b. l-ethyl-4-hydroxy-3-methyl-ll'l-pyrazolo[3,4- b]pyridine-5-carboxylic acid and ethyl ester 14.8 g.: of{['(l-ethyl-3-methyl-5-pyrazolyl)amino]- methylene]malonic acid diethylester (0.05 mol.) are dissolved in 50 g. of diphenyl ether. The reactionmixture is heated to 235-250 (bath temperature) and allowed to react atthis temperature for l to 2 hours, while the resulting ethanol iscontinuously distilled off. The last part ofthe alcohol is removed bymeans of water aspirator. The diphenyl ether. is separated bydistillation with a fractionating column in vacuo. Thelethyl-4-hydroxy-3-inethyl-1l-l-pyrazolo[3 ,4- b]pyridine-5-carboxylicacid ethyl ester is obtained at b.p. M 125l29, yield 10.7 g. 86 percentof theory, m.p. 9l93. The compound is recrystallized from benzine(90l00), m.p. 939 4. Hydrolysis of this product with aqueous sodiumhydroxide yields 1- ethyl-4-hydroxy-3-methyllH-pyrazolo[ 3 ,4-b]pyridine-5-carboxylic acid, m.p. 212-2l3.

c. 4-chloro-1-ethyl3-methyl-lH-pyrazolo[3 ,4- b]pyridine-5-carbonylchloride 22 g. of 1-ethyl-4-hydroxy-3-methyl1H-pyrazolo[3,4-b]-pyridine-5-carboxylic acid (0.1 mol.) and 75 ml. ofthionyl chloride are refluxed for 4 hours. The clear thionyl chloridesolution is evaporated to dryness in vacuo. The residue, weighing 24 g.(93 percent of theory), contains the crude 4-chlorol-ethyl-3methyl-1H-pyrazolo[3 ,4-b ]pyr'idine-5-carbonyl chloride, which can beused without further purification for the next reaction step. A samplerecrystallized from cyclohexane melts at 68-70.-

d. 4-[B-(4-chloro-1-ethyl-3-methyl-1l-l-pyrazolo[3,4-b]pyridine-5-formamido)ethyl]benzenesulfonamide 13 g. ofp-(B-aminoethyl)benzenesulfonamide (0.077 mol.) are added to a solutionof 9 g. of 4-chlorol-ethyl-3-methyll H-pyrazolo[ 3,4-b]pyridine-5-carbonyl chloride (0.053 mol.) in 100 ml. of anhydrouspyridine. After stirring the reaction mixture for 3 hours at roomtemperature, the precipitated p-(,6- aminoethyl) benzenesulfonamidehydrochloride is filtered off under suction and the filtrate isevaporated to dryness in vacuo. The residual product, 4[B-(4-chlorol-ethyl-3-methyll l-l-pyrazolo-[ 3,4-b]pyridine-5-formamido)ethyl]benzenesulfonamide is treated withwater, filtered under suction and recrystallized from amamido)ethyl]benzene-sulfonamide in the procedure of Example 1 (g).Yield 73 percent of theory, n 1.p. 2l7 -2l8.

EXAMBLlif l-Cyclohexyl-3-[[p-[2-(4-ethoxy-1-ethyl-3-methyl-1H-pyrazolo-[3,4-blpyridine-S-yl)formamido] ethyl]phenyl]sulfonyl]urea5.5 g. of l-cyclohexyl-3-[[p-[2-(4-chloro-1-ethyl-3- methyl-1H-pyrazolo[ 3 ,4-b]pyridin-5-yl)formamido] ethyl]phenyl]-sulfonyl]urea(0.01 mol.) are added to a solution of 0.5 g. of sodium (0.022 mol.) in75 ml. of ethanol. This mixture is kept at room temperature for 4 hours.After this time, the precipitate is filtered off under suction,washed'with absolute ethanol and anhydrous ether, and dissolved in 50ml. of water. The undissolved matter is separated by filtration and thefiltrate is acidified with dilute hydrochloric acid. The l-.cyclohexyl-3-[ [p-[ 2-(4-ethoxyl -ethyl-3-methyll H- pyrazolo- 3,4-b[pyridin-5 -yl )formamido ethyl phenyl]sulfonyl]urea, whichprecipitates in the form of crystals, melts after drying in thedesiccator and recrystallization from absolute ethanol at 186. The samecompound containing one mole of water has a melting point of l62-l64.Yield 4.7 g. 84.5 percent of theory. The sodium salt of l-cyclohexyl-3-l[p- [2-( 4-ethoxy- 1 -ethyl-3-methyl l H-pyrazolo 3 ,4-b]pyridin-5-yl)formamido]ethyl]phenyll-sulfonyl]urea is preparedaccording to the procedure of Example 1 EXAMPLE 5 4-[,8-(1-ethyl-3-methyl-1H-pyrazolo[3 ,4-b]pyridine-5-formamido)ethyl]benezenesulfonamide, m.p. 2l7-220, is obtained bysubstituting an equivalent amount of I 1-ethyl-3-methyl-l H-pyrazolo[3,4-b]

pyridine-S-carboxylic acid for the 4-ethoxy-1-ethyl- 1 H-pyrazolo[3,4-b]pyridine-5-carboxylic acid in the procedure of Example 2(c). This may in turn be converted to l-cyclohexyl-3-[ [p-[-2-(1-ethyl-3-methyl-1H- pyrazolo[ 3,4-b]-pyridine-5-yl)formamido]ethyl]phenyl]sulfonyl]urea according. tothe procedure in Example 1 (g), m.p. l92-194 (methanol). The sodium saltof this product which is prepared according to the procedure of Example1 .(g), contains l/2 mole of water, m.p. z 295.

The following additional compounds are produced by the procedure ofExample 1:

l 0 RP -l lLmr-om-cmsor-N11 d-NH- s MP, sodium M.P. salt (deg.) ExampleR; Ra Ra (deg) decomp. 6 CHz-OH; H OH --O 7 CH2CH1 CH3 CH -O 8.. CHa-CH,CH3 (CHzhCH-O U CHr-CIh-CHg-CH; CH3 O1 EXAMPLE 12wethyl]phenyl]sulfonyl]urea is obtained.

The following additional compounds are produced by the procedure ofExample 1 by replacing the lethyI-S-amino-pyrazole in part a with theappropriately razolo[3 ,4-b]-pyridin-5 -yl)formamido]ethyl]phenyl]sulfonyl]urea H I W m By substituting 0.01 mole of cyclopentylisocyanate25 substituted S-aminopyrazole for the cyclohexylisocyanate in theprocedure of Example l (g),l-cyclopentyl-3-[[p-[2-[(4-ethoxy-l-ethyllH-pyrazolo[3,4-b]-pyridin:yl)formamido] ample 3.

replacing the cyclohexylisocyanate with cyclopentyl isocyanate in partg. The halogenated compounds are made as in Ex- Example R R; R:

20 CzH5 H CHaO 2 Q H z s 22 t f E CH (371150 23 E Ugl'l Bl 2 Q cz s 25or H ogHfio 26 CHaO 0 H; C3H70 l CHaO 27 H Cl 28 H Cl 29 CH CH 021150Example R CHaO- CH:

The following additional compounds are produced by the procedure ofExample 1 (or halogen) by replacing the l-ethylpart a with theappropriately Example 3 where R S-aminopyrazole in substituted 5- CH3CHaO aminopyrazole and, where appropriate, replacing thecyclohexylisocyanate with the appropriate R -isocyanater u ll m-CNHCHzCH s O NHCNHR R1 Example R1 R1 R3 R4 32 R C 33 CH3 H' -CH:

01 Q c1 Q C1 (5) 36 G1H5 H CHaO s l 37 Q H z n 02 33 .r G CH3 CzHsOi-C3H7 39 "Q CzHs C4Ho 40 G 02115 B Ci ia 41 01 H CzHgO CH3 l C1 42 V-C1130 C 115 C H O C Hn l CHsO 43 CH CHO H C 3 2 a z 5 C: 5

44 H C1 04H! 45 CH CH3 CIHEO CA B l CH 46 H CHg=CHCH2O CaH1 47 C1115 CH3What is claimed is: l. A compound of the formula lower alkyl, halogen orlower alkoxy, and n is 1 or 2,

and physiologically acceptable salts thereof.

2. A compound as in claim 1 wherein R4 is cyclohexyl.

3. A compound as in claim 2 wherein R and R each is lower alkyl and R islower alkoxy.

4. A compound as in claim 2 wherein R is lower alkyl, R is hydrogen andR is lower alkoxy.

5. A compound as in claim 2 wherein R and R each is lower alkyl and R ishalogen.

6. A compound as in claim 2 wherein R, is ethyl, R is hydrogen and R isethoxy.

7. A compound as in claim 2 wherein R is ethyl, R is ethyl and R ischlorine.

8. A compound as in claim 2 wherein R, is ethyl, R is methyl and R isethoxy.

9. A compound as in claim 2 wherein R, is ethyl, R is methyl and R ishydrogen.

2. A compound as in claim 1 wherein R4 is cyclohexyl.
 3. A compound as in claim 2 wherein R1 and R2 each is lower alkyl and R3 is lower alkoxy.
 4. A compound as in claim 2 wherein R1 is lower alkyl, R2 is hydrogen and R3 is lower alkoxy.
 5. A compound as in claim 2 wherein R1 and R2 each is lower alkyl and R3 is halogen.
 6. A compound as in claim 2 wherein R1 is ethyl, R2 is hydrogen and R3 is ethoxy.
 7. A compound as in claim 2 wherein R1 is ethyl, R2 is ethyl and R3 is chlorine.
 8. A compound as in claim 2 wherein R1 is ethyl, R2 is methyl and R3 is ethoxy.
 9. A compound as in claim 2 wherein R1 is ethyl, R2 is methyl and R3 is hydrogen. 